The management of metastatic breast cancer remains a therapeutic challenge (DeSantis et al., (2011) Ca-Cancer J. Clin. 61: 409-418). An ideal cancer treatment should not only cause tumor regression and eradication but also induce a systemic antitumor immunity for control of metastatic tumors and long-term tumor resistance. This can be achieved by using the immune system as a weapon to recognize the tumor antigen so that once the primary tumor is eliminated, metastases will also be destroyed. Earlier success in applying the immune system to metastatic cancer, as well as the limited contributions from conventional chemo or radiation therapy makes metastatic cancer a focus for contemporary development of novel treatment options (Turcotte& Rosenberg (2011) Adv. Surg. 45: 341-360). The main pillars of cancer treatment chemotherapy, surgery, and radiation therapy are known to suppress the immune system (Castano et al., (2006) Nat. Rev. Cancer. 6: 535-545). The only cancer treatment that stimulates anti-tumor immunity is photodynamic therapy (PDT) (Castano et al., (2006) Nat. Rev. Cancer 6: 535-545; Gollnick et al., (2006) Laser Surg. Med. 38: 509-515). Photodynamic therapy involves administration of a photosensitizer (PS) followed by illumination of the tumor with a long wavelength (600-800 nm) light producing reactive oxygen species (ROS) resulting in vascular shutdown, cancer cell apoptosis, and the induction of a host immune response (Dougherty et al (1998) J. Natl. Cancer Inst. 90: 889-905). The exact mechanism involved in the PDT-mediated induction of anti-tumor immunity is not yet understood. Possible mechanisms include alterations in the tumor microenvironment by stimulating pro-inflammatory cytokines and direct effects of photodynamic therapy on the tumor that increases immunogenicity (Castano et al., (2006) Nat. Rev. Cancer. 6: 535-545). Photodynamic therapy can increase dendritic cells (DC) maturation and differentiation, which leads to the generation of tumor specific cytotoxic CD8 T cells that can destroy distant deposits of untreated tumor (FIG. 1) (Castano et al., (2006) Nat. Rev. Cancer. 6: 535-545; M. Korbelik, (2011) Photoch. Photobio. Sci. 10: 664-669; van Duijnhoven et al., (2003) Photochem. Photobiol. 78: 235-240; A. Oseroff (2006) J. Invest. Dermatol. 126: 542-544).
There are increasing number of studies showing that immunoadjuvants when injected intratumorally can produce a similar infiltration of leukocytes into the tumor (Castano et al., (2006) Nat. Rev. Cancer. 6: 535-545). Immunoadjuvants are frequently prepared from microbial cells and are thought to act via Toll-like receptors (TLRs) (Werling & Jungi (2003) Vet Immunol. Immunopathol. 91: 1-12) present on macrophages and dendritic cells (DCs). This indicates that a combination of photodynamic therapy with a DC activating agent that can act as an agonist of TLR might be promising for the treatment of metastatic tumor. There are few reports of combinations of photodynamic therapy with microbial derived products potentiating tumor response and leading to long-term anti-tumor immunity (Castano et al., (2006) Nat. Rev. Cancer. 6: 535-545; Gollnick & Brackett (2010) Immunol. Res. 46: 216-226). However, thus far administrating the immunoadjuvants as separate constructs by intratumoral injection has only been explored to combine photodynamic therapy with immunotherapy (Qiang et al., (2008) Med. Res. Rev. 8. 632-644; T. G. St Denis (2011) Photoch. Photobio. Sci 10. 792-801). Nanotechnology-based differential combination therapy can be emphasized as a promising strategy for metastatic breast cancer.